Version May 2024
INTRODUCTION — Understanding the natural history of food allergy in childhood is essential in managing patients with these disorders. The natural history of a food allergy includes information on the acquisition of the allergy, the likelihood that it will be outgrown, and its usual duration.
Food allergy most often begins in the first two years of life. Certain food allergies, such as those to cow's milk (CM) and hen's egg (HE), are usually outgrown during childhood or adolescence, whereas peanut and tree nut allergies are more likely to persist into adulthood or may develop in later childhood or adulthood.
This topic review provides an overview of the natural history of food allergy in children and is focused on immunoglobulin E (IgE) mediated allergy. Food allergy in adults is reviewed separately. The clinical manifestations and treatment of food allergy are also discussed separately. (See "Food intolerance and food allergy in adults: An overview" and "Clinical manifestations of food allergy: An overview".)
TERMINOLOGY — The term "food allergy" refers to an abnormal immunologic reaction to a food that results in the development of symptoms on exposure to that food. This clinical reactivity is assessed by history or challenge. Such reactions can be mediated by IgE antibodies directed against specific food proteins that activate mast cells and basophils or can arise from other cellular processes involving eosinophils or T cells. (See "Clinical manifestations of food allergy: An overview".)
The term "sensitization" is used to denote the presence of IgE directed against a specific antigen (a "positive" test), as detected by in vivo (skin prick test [SPT]) or in vitro (fluorescent-enzyme immunoassay [FEIA]) testing. However, a patient who is sensitized to a particular food may not be clinically reactive upon exposure to the food. Less commonly, a patient may have a clear history of food-allergic reactions with low or undetectable levels of food-specific IgE.
PREVALENCE OF CHILDHOOD FOOD ALLERGY — Up to one-third of parents/caregivers report adverse food reactions in their young children, although the rates of verifiable food allergy are much lower [1-6]. Nonimmunologic adverse reactions account for the bulk of adverse food reactions. Food sensitization and/or allergy occur in approximately 5 to 10 percent of young children, with peak prevalence at approximately one year of age. However, studies that measure sensitization to food allergens can overestimate the prevalence of true allergic reactions to foods because not all sensitized children will develop symptoms upon ingestion. (See 'Terminology' above and "Diagnostic evaluation of IgE-mediated food allergy".)
Most food allergy is acquired in the first or second year of life. The peak prevalence of food allergy is approximately 6 to 8 percent at one year of age, although reported rates of oral food challenge (OFC) confirmed food allergy are as high as 11 percent [7-15]. Prevalence then falls progressively until late childhood, after which it remains stable at approximately 3 to 4 percent [9,10,12,16]. Some studies have suggested that the prevalence of food allergy has increased over time.
The following studies are illustrative:
●The prevalence of parentally reported food allergy in children (aged 0 to 17 years) in the National Health Interview Survey has slowly increased in the United States, from 3.4 percent in 1997 to 1999, to 5.1 percent in 2009 to 2011 [17], and 6.2 percent in 2016 [18], although there are signs that it may be leveling out, as the rate was 5.8 percent in 2021 [19].
●Parentally reported adverse food reactions were assessed with a prospective study of 3623 children followed from birth until the age of two years in Norway [1,2,20]. Parents completed questionnaires at six-month intervals. The cumulative incidence of adverse food reactions was 35 percent by age two years. Cow's milk (CM), fruits (especially citrus and strawberry), and vegetables (especially tomato) accounted for nearly two-thirds of all reported reactions, with a cumulative incidence of 12 percent for CM. Other problematic foods reported by parents included hen's egg (HE; 4.4 percent), fish (3 percent), "nuts" (2.1 percent), and cereals (1.4 percent). The overall duration of food reactivity was short, with approximately two-thirds of the reactions resolving within six months of their onset. The probable explanation for the brief duration of most of these reactions is the commonplace nature of irritant, nonimmunologic food reactions in infants and young children. Mild perioral rashes after eating tomatoes or berries are examples, although IgE-mediated allergies to these foods are also possible.
●The German Multicenter Allergy Study followed the development of sensitization to common food allergens without clinical confirmation of food reactions in a large cohort of children [21-23]. A total of 216 children from a birth cohort of 4082 children were assessed with serum food-specific IgE testing approximately yearly. The overall annual incidence rates for food sensitization decreased from a peak of 10 percent at age one year to 3 percent at age six years. Sensitization to HE and CM were most common, with peak prevalence rates of approximately 6 percent at age one year, followed by wheat and soy. A Danish study that followed 276 children showed similar results, with approximately 6 percent sensitized to CM and/or HE at 1.5 years, rising to approximately 14 percent at 5 years, and falling to 5 percent or less at 10, 15, and 26 years [24,25].
●In an Australian birth cohort, the prevalence of sensitization to peanut, HE, and sesame during the first year of life was 8.9, 16.5, and 2.5 percent, respectively, whereas the prevalence of challenge-proven allergy to these same foods was 3.0, 8.9, and 0.8 percent, respectively [7]. Similarly, in a European birth cohort, the prevalence of sensitization during the first two years of life was 2.9 percent, but challenge-proven allergy was 0.5 percent [26].
●The prevalence of doctor-diagnosed food allergy in children with a consistent clinical history and confirmatory testing was examined in a population-based cohort in Olmsted County, Minnesota from 2002 through 2011 [27]. The incidence of pediatric food allergy increased from 7.0 per 10,000 person-years in 2002 to 2003 to 13.3 per 10,000 person-years in 2006 to 2007 and then leveled off at approximately 12 per 10,000 person-years in the final two calendar periods.
ASSOCIATION WITH SUBSEQUENT ASTHMA AND ALLERGIC RHINITIS — Young children who are sensitized to foods or have confirmed IgE-mediated food allergy are more likely than their nonallergic peers to develop allergic rhinitis and asthma later on. This association between early food allergy and later atopic respiratory conditions has been noted in multiple studies [21,28-30] and is similar to that seen with atopic dermatitis. (See "The relationship between IgE and allergic disease", section on 'The atopic march'.)
A meta-analysis of birth cohorts found that early life food sensitization was associated with approximately three times the odds of wheeze/asthma (odds ratio [OR] 2.9) and allergic rhinitis (OR 3.1) at ages four to eight years [31]. In the Australian birth cohort mentioned above, food challenge-confirmed food allergy at one year of age was associated with a more than twofold risk of asthma diagnosis at age four years compared with those children not sensitized to foods (asthma prevalence of 23.9 percent compared with 11.5 percent) [32]. This risk persisted even if the food allergy resolved.
OVERVIEW OF RESOLUTION — The majority of childhood food allergies are lost over time, although the process of resolution varies a great deal among different foods and individual patients. (See 'Natural history of specific allergies' below.)
Mechanisms — The mechanisms by which food allergy resolves are not fully understood, and multiple mechanisms are probably involved. Food-specific IgE levels tend to fall over time in most patients with food allergy. This loss of IgE is the best known predictor of the development of clinical tolerance [33-35]. However, it is also clear that some patients become tolerant even with persistently elevated food-specific IgE levels and ongoing positive skin prick tests (SPTs). Thus, loss of IgE is not a requirement for, or even the primary mechanism of, the resolution of food allergy in these patients. Other humoral changes, including increased levels of allergen-specific immunoglobulin G4 (IgG4) and/or mucosal immunoglobulin A (IgA), may also play a role. Alternately, cellular changes, such as the induction of T regulatory cells, may be important.
Role of avoidance — Strict dietary avoidance of the foods to which a child is allergic has been a mainstay of food allergy management. The primary reason for avoidance is prevention of reactions. Strict avoidance is usually advised, rather than having patients ingest an allergen in subthreshold amounts, because patients may accidentally consume a larger amount than intended and elicit an allergic reaction. (See "Management of food allergy: Avoidance", section on 'How strict must avoidance be?' and 'Determining if an allergy has resolved' below.)
It was also hoped that strict avoidance might increase the chance of outgrowing an allergy or hasten resolution. However, there were few studies to support this idea, and at least one study that found that neither strict avoidance nor accidental ingestion was associated with acquisition of tolerance [36-38]. In addition, results from subsequent studies have suggested that regular exposure to extensively heated cow's milk (CM) and hen's egg (HE) in children who tolerated the more processed forms of these allergens shortens the time to resolution of the allergy [39-41]. (See 'Role of baked milk in resolution of CMA' below and 'Role of baked egg in resolution of egg allergy' below.)
It is not known whether intermittent trace consumption of allergen has any effect on resolution of allergy. In one study of young children, exposures to CM, HE, or peanut resulting in allergic reactions during food challenges or accidental ingestion did not appear to cause increases in sensitization [42].
Some patients demonstrate sensitization to a food that they consume (eg, a positive allergen SPT or elevated serum food-specific IgE), but they do not have a clear history of reactions to that food. Several small case series have reported that invoking strict avoidance of the food occasionally results in acute and severe reactions to the self-same food upon intentional or accidental reintroduction [43-46]. This phenomenon may represent a loss of a desensitized state to a food that was maintained while it was regularly ingested. While there are no formal studies assessing the risk of occurrence of this uncommon outcome, decisions regarding removal of foods from the diet (eg, in patients with suspected food-triggered atopic dermatitis) need to consider this possibility. No foods should be removed from the diet based solely upon a positive blood test or SPT result (ie, based upon sensitization alone). (See "Diagnostic evaluation of IgE-mediated food allergy", section on 'Role of allergy tests in diagnosis' and "Role of allergy in atopic dermatitis (eczema)", section on 'Food allergies' and "Oral food challenges for diagnosis and management of food allergies".)
Monitoring the child with food allergy — The child with food allergy must be followed regularly by both the pediatrician and allergy specialist to assure that growth is normal and that adequate nutrition is provided. Consultation with a dietitian can help further education regarding allergen avoidance and adequate food substitutes. This may be necessary if there are many foods to be avoided and if there is slowing of growth. The allergy specialist should review all accidental exposures and food reactions in order to assure that avoidance measures are adequate, reactions are recognized promptly and treated appropriately, epinephrine autoinjectors are current and available to the child in all settings (if appropriate), and that the patient and caregivers understand the management plan. Just as importantly, accidental exposures that did not result in reactions should be assessed with hopes that the allergy is resolving.
Serial testing — The allergy specialist should evaluate the child at regular intervals to determine if the allergy has been outgrown. Reevaluation can be accomplished with in vitro and/or SPT and information on accidental exposures. Reevaluation is usually performed yearly; however, longer or shorter intervals may be more appropriate in some situations [47]. As an example, a young child with a reaction to fruit might be evaluated every six months because reactions to fruit at this age are not necessarily due to true allergy and, even if they are, are quickly outgrown. In contrast, a 10 year old with peanut allergy (typically a lifelong allergy) whose tests remain elevated may only be tested every few years. In general, the higher the food-specific IgE level or the larger the SPT wheal, the less likely the child is to become tolerant in the short term. However, many young children will outgrow their allergy to foods such as CM and HE later in childhood or adolescence.
The optimal testing method of monitoring specific food allergies has not yet been determined. Thus, various approaches are used. Some centers use in vitro testing (eg, fluorescent-enzyme immunoassay [FEIA] such as ImmunoCAP) in addition to clinical history to follow patients, whereas others use skin testing. Still other centers use both types of testing, especially when making decisions about whether or not to proceed to an oral food challenge (OFC). Testing for allergic disease is reviewed separately. (See "Overview of in vitro allergy tests" and "Overview of skin testing for IgE-mediated allergic disease" and "Diagnostic evaluation of IgE-mediated food allergy" and "Oral food challenges for diagnosis and management of food allergies".)
Determining if an allergy has resolved — Neither in vitro testing nor SPT is perfect in determining resolution of a food allergy. Negative tests do not guarantee loss of allergy with absolute certainty, and positive tests can persist even after a patient has developed tolerance to a food [48,49]. Thus, a clinician-supervised OFC is often required to prove that the allergy has resolved. As an example, it is usually reasonable to proceed with an OFC to determine if the allergy has resolved in a patient who has tolerated a larger accidental exposure, even if in vitro or SPT results have not improved. OFCs must be performed with caution and should be performed only by an allergy specialist with full emergency equipment and medications on hand to treat possible reactions. (See "Oral food challenges for diagnosis and management of food allergies".)
Factors associated with a higher odds of passing a challenge include:
●Lower food-specific IgE levels or smaller SPT wheal size (cutoffs vary from food to food and may be lower for young children)
●Downward trends over time in food-specific IgE or SPT wheal size, even if the levels are still relatively high
●Absence of an interval history of symptoms triggered by accidental exposure
●Fewer failed OFCs, longer interval since last failed OFC, and failure at a higher dose
Another factor to consider is whether cross-reactivity with another allergen is influencing the level of reactivity on a test. (See "Food allergens: Clinical aspects of cross-reactivity".)
As an example, soy allergy is typically outgrown more quickly than allergy to other common foods such as CM and HE. Thus, blood and/or skin testing is often performed yearly. Challenge is usually offered when the results of in vitro testing have reached levels of ≤20 kU/L, although some patients with peanut allergy may have far higher levels due to cross-reactivity between peanut and soy on in vitro testing. The approach to monitoring and testing for resolution for individual food allergens is discussed in the allergen-specific topics.
NATURAL HISTORY OF SPECIFIC ALLERGIES — Issues relating to prevalence, resolution, and recurrences of food allergy are best understood with respect to the specific food. The most reliable information concerns allergies to cow's milk (CM), hen's egg (HE), peanut/tree nuts, and wheat. The natural history of other food allergies, such as allergies to soy and sesame, has been less well studied.
Cow's milk — Cow's milk allergy (CMA) is the most common food allergy among infants and young children. Resolution is gradual throughout childhood and adolescence and is influenced by various factors. Patients are typically reevaluated yearly, with clinical history and in vitro and/or skin prick testing (SPT).
The diagnosis and management of IgE-mediated CMA is discussed in greater detail separately. (See "Milk allergy: Clinical features and diagnosis" and "Milk allergy: Management".)
Non-IgE mediated forms of CMA are also discussed separately. (See "Food protein-induced allergic proctocolitis of infancy" and "Food protein-induced enterocolitis syndrome (FPIES)" and "Clinical manifestations and diagnosis of eosinophilic esophagitis (EoE)" and "Dietary management of eosinophilic esophagitis".)
Prevalence — CMA affects approximately 0.5 to 2.5 percent of children during the first two years of life, with lower rates reported for allergy confirmed by oral food challenge (OFC) compared with self-reported allergy [11,13,15,26]. Much of reported CMA is non-IgE mediated. A large Danish study published in 1990 confirmed CMA in 2.2 percent of children followed to age three years but noted that nearly one-half of the cases were non-IgE-mediated allergic conditions, such as dietary protein-induced proctitis/colitis, enteropathy, and enterocolitis [28]. Up to 50 percent of children with CMA also have concomitant adverse reactions to other foods [50]. (See "Food protein-induced allergic proctocolitis of infancy".)
Resolution — The resolution of CMA is variable, depending upon the type of allergy (IgE mediated or non-IgE mediated) [28,48,50] and the population examined (general public or referral populations) [28,33,40,51]. Non-IgE-mediated CMA tends to resolve more quickly. The common CM protein-induced proctocolitis typically resolves by one year of age, and, for this condition, CM can be introduced at home. For food protein-induced enterocolitis syndrome (FPIES), a careful OFC supervised by an allergy specialist in a setting appropriate for a high-risk procedure is warranted by the age of two to three years if there have been no recent reactions from accidental exposures. Challenges in patients with FPIES who were very ill upon presentation should be performed under close supervision in a hospital setting. Concomitant allergic rhinitis and asthma and onset of the allergy at less than one month of age are risk factors for persistent IgE-mediated food allergies. Introduction of extensively heated CM may speed resolution of IgE-mediated CMA [52]. (See "Food protein-induced enterocolitis syndrome (FPIES)" and "Milk allergy: Management", section on 'Extensively heated (baked) cow's milk'.)
Resolution rates for IgE-mediated CMA are significantly lower than those of non-IgE-mediated CMA, although there are little data on population trends in resolution in the era of widespread testing for tolerance of extensively heated milk. One study followed 98 children (median age 24 months) with CMA (two-thirds with IgE-mediated allergy) for a median of two years (range: 6 to 72 months) [48]. Development of tolerance occurred in 22 percent of those with IgE-mediated allergy compared with 59 percent of those with non-IgE-mediated CMA. In another study of 139 children with CMA (half with IgE-mediated allergy) followed for an average of seven years, CMA resolved in 34 percent by age 2 years, 55 percent by age 5 years, and 68 percent by age 10 years [53]. However, tolerance was delayed in the subgroup of children with IgE-mediated CMA, with resolution occurring in none of these children by age 2 years, 22 percent by age 5 years, and 43 percent by age 10 years.
Resolution rates vary in different study populations. Rates of resolution in children with IgE-mediated CMA followed in allergy practices are lower than those of children in the general population, probably because these children are more severely allergic, although other confounders have not been excluded. One large, retrospective study reported resolution rates in 807 children with CMA who were followed by allergy specialists [40]. If resolution was defined as passing an OFC or having a cow's milk-specific IgE (CM-IgE) of <3 kUA/L and no reactions within the past year, CMA resolved in 19, 42, 64, and 79 percent of children at ages 4, 8, 12, and 16 years, respectively. In contrast, 76 percent of children with IgE-mediated CMA in the previously described Danish study recruited from the general population were tolerant by age three years [28].
Finally, several clinical features are associated with persistent IgE-mediated CMA, including reactivity to baked CM products; the presence of concomitant allergic rhinitis, asthma, or moderate-to-severe atopic dermatitis; and onset of the allergy in the first month of life [33,40,51,54]. As an example, an Israeli study followed 105 children with CMA for a period of eight years [54]. Sixty-one percent of patients with persistent CMA had asthma compared with 19 percent in the resolution group. However, this association may just reflect the fact that these children were followed later into childhood than children whose allergy had resolved.
Role of baked milk in resolution of CMA — Several studies have suggested that introduction of baked CM products may increase the likelihood of cow's milk allergy (CMA) resolution and/or speed the process (see "Milk allergy: Management", section on 'Extensively heated (baked) cow's milk'):
●In a study of 88 children with CMA who were challenged to baked CM, subjects who were initially tolerant to baked CM were 28 times more likely to become tolerant to liquid milk over a median of 37 months than those who were initially baked CM reactive, with 60 percent of those who passed a baked CM challenge progressing to tolerating unheated CM by the end of the study period [55].
●In a study of 170 children with CMA (average age seven years), 48 percent of those who introduced baked CM were able to consume liquid CM within three years compared with none of those reactive to baked CM at baseline and continued avoidance and none of those who qualified for inclusion but chose not to take part in the active study [56].
Cow's milk-specific IgE and SPT — In general, the higher the CM-IgE, the less likely the child is to become tolerant over time. In the retrospective study discussed previously, persistence was more likely in patients with higher initial levels of CM-IgE [40]. Median CM-IgE in the first two years of life was 19 kUA/L in the children with CMA that persisted compared with 1.8 kUA/L in those with CMA that eventually resolved [40]. In addition, CM-IgE levels in persistent CMA tended to increase over the first three to four years of life and then gradually decrease, while those in resolving CMA were stable initially and then gradually declined. Similarly, in a prospective series of 293 children aged 3 to 15 months with CMA, 72 percent (88 of 122) with a baseline CM-IgE <2 kUA/L had resolved CMA compared with only 23 percent (19 of 82) of those with baseline CM-IgE ≥10 kUA/L [33]. Similar results were found with CM-SPT. Approximately 45 percent of those with a baseline CM-SPT ≥10 mm had resolved CMA compared with approximately 80 percent of those with a CM-SPT <5 and 60 percent of those with a CM-SPT between 5 and 10 mm.
Another study examined the rate of change in levels of CM-IgE over time, in relation to the patient's age, in children who developed CMA before the age of four years [57]. CM-IgE levels decreased more rapidly in those who developed tolerance. Independent of initial levels, the percentage amount that CM-IgE dropped in one year correlated with the likelihood that the child would pass an OFC performed at that time. If the CM-IgE dropped 50, 75, 90, and 99 percent, there was a 31, 45, 66, and 95 percent chance of passing the OFC, respectively. For CM-SPT, declining SPT wheal size over time is also predictive of resolution [33].
IgE antibodies are not equally pathogenic, and IgE directed against certain types of epitopes may be associated with persistent allergy [58-60]. Some studies have shown that IgE directed against certain CM epitopes may distinguish between persistent and resolved CMA [58-61]. However, IgE levels to specific CM proteins, such as casein, alpha-lactalbumin, and beta-lactoglobulin, are not superior to IgE to CM. (See "Component testing for animal-derived food allergies", section on 'Cow's milk'.)
Hen's egg — Hen's egg allergy (HEA) is one of the most common food allergies of childhood. The presence of HEA is a marker for subsequent sensitization to aeroallergens, as well as the later development of asthma [21,62]. As with CMA, it is frequently outgrown during childhood or adolescence, and introduction of baked HE may speed resolution of HEA. Patients are typically reevaluated yearly, with clinical history and in vitro testing and/or SPT. Egg-specific IgE (E-IgE) levels may indicate probability of resolution and the likelihood that a child has outgrown the sensitivity.
The diagnosis and management of HEA are discussed in greater detail separately. (See "Egg allergy: Clinical features and diagnosis" and "Egg allergy: Management".)
Prevalence — HEA affects 1 to 9 percent of young children [8,20]. In the US, the rate of self-reported HEA among children is 0.6 to 0.8 percent overall and 1 percent among those zero to two years old [13,15]. However, the rate of HEA may be higher than what is captured by survey; in a multicountry European birth cohort (EuroPREVALL) where clinical symptoms of food allergy triggered a full evaluation, the rate of HEA was 1.2 percent among one to two year olds, while, in Australia, in the population-based HealthNUTs study where all children were skin tested, a full 9 percent of one year olds had OFC-proven HEA [7,63]. This surprisingly higher rate in a study with universal SPT screening may reflect the fact that many children with allergy to uncooked HE tolerate heated forms and that much early HEA is transient. Most reactions are IgE mediated.
Resolution — HEA usually resolves within several years of diagnosis but is slower in certain populations [34,39,57,64-68]. As with CMA, tolerance of extensively heated (baked) HE predicts increased rate of resolution, and introduction of baked HE may speed resolution of HEA. (See 'Role of baked egg in resolution of egg allergy' below.)
In two population-based studies, HEA resolved in 45 to 47 percent of children by age two years [67,68], and 71 and 89 percent by six years [67,69]. In contrast, a retrospective study of 881 children with HEA followed by allergy specialists found that resolution was slower in this referral population [39]. When resolution was defined as passing an OFC procedure involving the ingestion of one whole, cooked HE, HEA resolved in 4, 26, 48, and 68 percent of children at ages 4, 8, 12, and 16 years, respectively.
Role of baked egg in resolution of egg allergy — Tolerance to HE in baked goods is common and typically occurs at an earlier age than tolerance to lightly cooked or raw HE [39,70-72]. In one series of children with HEA, the median age of tolerance to well-cooked HE was 5.6 years versus a median of 10.3 years for uncooked HE [72]. As with CMA, there is evidence that tolerance of HE in baked goods may increase the likelihood of HEA resolution and may hasten the process [71]. (See 'Role of baked milk in resolution of CMA' above.)
●In an Australian study, the rate of resolution of HEA at two years was 56 percent in those who tolerated baked HE at one year and 13 percent in those who were reactive to baked HE [68].
●In a study of 79 subjects with HEA followed for a median of 38 months, 64 percent of those who initially tolerated baked HE tolerated regular HE at the end of follow-up compared with 26 percent of those who were reactive to baked HE [73].
Egg-specific IgE and SPT — E-IgE and skin prick testing (SPT) levels decrease more rapidly in those children who develop tolerance than in those with persistent allergy, as with CMA [57]. In a group of children who developed food allergy before the age of four years [68], the percentage amount that E-IgE dropped in one year correlated with the likelihood that the child would pass an OFC performed at that time. If the E-IgE dropped by 50, 75, 90, or 99 percent, the chance of passing an OFC was 52, 65, 78, or 95 percent, respectively. An E-IgE level ≥50 kUA/L was a marker of persistent HEA in one study population [39]. In a different prospective study of infants followed to six years, baseline HE SPT was also predictive of resolution of allergy: 46 percent of those with an HE SPT wheal >5 mm at baseline had resolved allergy compared with 60 percent of those with an HE SPT wheal <5 mm [34]. In the population-based Australian study, smaller HE SPT was associated with higher rate of resolution by six years but was only weakly predictive of outcome [69].
Peanut and tree nuts — Peanut and tree nut allergies are frequently studied together as they coexist in up to 30 to 40 percent of patients [74-76]. More information is available on the natural history of peanut allergy, and the understanding of it is changing. Peanut and tree nut allergy affects at least 0.5 to 3 percent of children and may be increasing over time. Although it was initially believed to be a lifelong sensitivity in nearly all cases, subsequent studies have shown that tolerance can develop in approximately 20 to 30 percent of patients. Less is known about tree nut allergy, although a minority of patients appear to lose this sensitivity as well.
The diagnosis and management of peanut and tree nut allergy are discussed in greater detail separately. (See "Peanut, tree nut, and seed allergy: Clinical features" and "Peanut, tree nut, and seed allergy: Diagnosis" and "Peanut, tree nut, and seed allergy: Management".)
Prevalence — Many studies from the United States and Europe have estimated the prevalence of peanut and tree nut allergies at 0.4 to 1.3 percent in children and 0.5 to 1 percent in the overall population [74,75,77-80]. As an example, a meta-analysis of peanut allergy in Europe that included clinical history and OFCs found a rate of peanut allergy of 1.6 percent, although there were large geographic variations [11]. In population-based Australian studies of 1 year olds conducted between 2007 and 2011 and 10 to 14 year olds surveyed between 2011 and 2014, the rate of peanut allergy was 3 percent and 2.7 percent, respectively [81,82]. Using a similar design, the same group again assessed the rate of peanut allergy among one year olds in Australia in 2018 to 2019, after new guidance to introduce peanut, and did not find a statistically significant change in the rate of peanut allergy in a standardized population (2.6 percent) [82]. The rate of tree nut allergies varies widely throughout the world. In a systematic review, the prevalence of tree nut allergies in children was 0 to 1.4 percent when confirmed by OFC, 0 to 4.9 percent by self-report, and 0.8 to 6.5 percent based upon sensitization. In Europe, hazelnut allergy was most commonly reported, while Brazil nut, almond, and walnut were most common in the United Kingdom and walnut and cashew in the United States [83,84]. (See "Peanut, tree nut, and seed allergy: Clinical features".)
Serial studies in the United Kingdom and the United States have suggested that the prevalence of peanut allergy is increasing over time [75,79,85]. In a random calling telephone survey conducted in the United States, the reported prevalence of peanut allergy in children increased from 0.4 in 1997 to 0.8 percent in 2002 and 1.4 percent in 2008 [75,86]. In a study in Olmstead, Minnesota, the estimated rate of peanut allergy based upon medical records rose from 0.2 percent in 1999 to 0.7 percent in 2007 [87]. In two Isle of Wight birth cohort studies in the United Kingdom, 0.6 percent were diagnosed with peanut allergy at 10 years of age in the 1989 cohort compared with 1.4 percent in the cohort enrolled between 2001 and 2002 [88]. However, studies that incorporate measures of sensitization have not shown the same increase. Rates of IgE sensitization to peanut were steady among US children in the National Health and Nutrition Examination Survey (NHANES) between 1988 and 1994 and 2005 and 2006 [89], as were rates of SPT sensitization to peanut between two Melbourne cohorts born between 1990 and 1994 and 2006 and 2010 [90]. It is not clear why trends in sensitization do not match trends in diagnosis of food allergy [91].
Resolution — A substantial minority of patients (ie, 20 to 30 percent for peanut and 9 percent for tree nuts) lose their sensitivity over time.
●Peanut – Early studies suggested that peanut allergy was persistent [92]. However, subsequent data have revealed that up to 30 percent of patients become tolerant over time [35,69,76,78,93,94]. Smaller baseline peanut SPT and lower peanut IgE (PN-IgE) levels are associated with higher likelihood of resolution [78,93,95].
●Tree nuts – Few data exist concerning the resolution of tree nut allergy. In one study that used a double-blind, placebo-controlled food challenge (DBPCFC) to confirm the loss of clinical reactivity, the resolution of tree nut allergy was estimated to be at least 9 percent (9 of 101 children) [96]. The rate of resolution increased with lower tree nut IgE (TN-IgE) levels (58, 63, and 75 percent of children with TN-IgE levels <5 kUA/L, <2 kUA/L, and negative [<0.35 kU/L] TN-IgE levels, respectively).
Prognostic factors — The results of serial objective testing appear to be the best indicator of resolution or persistence of peanut allergy (see 'Monitoring the child with food allergy' above):
●An Australian study of 267 children referred to a specialty center and diagnosed with peanut allergy before the age of two years found that a positive SPT wheal ≥6 mm in diameter or a PN-IgE ≥3 kUA/L before the age of two years were independent predictors of persistent allergy at age eight years [94]. Patients whose allergy eventually resolved tended to have positive SPTs of decreasing size between ages one and four years, while patients with persistent allergy typically had increasingly larger positive SPTs.
●A prospective Canadian study of 202 children with onset of peanut allergy at 18 months of age or younger (median age 12 months) examined the natural evolution of the disease into adolescence (median age 13 years) [95]. Factors associated with persistence included progressively increasing PN-IgE and SPT wheal and initial PN-IgE >0.7 kUA/L. Resolution was associated with a continued low PN-IgE and decreasing SPT wheal between one and four years of age.
●A population-based Australian study of 139 peanut-allergic children with OFCs at one and four years of age found that small SPT size and lower PN-IgE levels at baseline were associated with higher likelihood of resolution [35]. Peanut SPT of 13 mm or greater or PN-IgE of 5 kU/L at one year old were associated with 95 percent change of persistent peanut allergy at four years, while an SPT of 2 mm or less was associated with 50 percent likelihood of resolution and a PN-IgE of 0.35 kU/L or less with a 43 percent likelihood of resolution. Levels of IgE to the peanut component Ara h2 were not predictive of resolution.
Studies evaluating the resolution of both peanut and tree nut allergy also suggest the following:
●Low or undetectable specific IgE levels or small SPT were the best predictors of a negative challenge.
●Clinical features do not reliably predict persistence; neither the presence of other atopic diseases, age at diagnosis, nor the severity of initial peanut or tree nut reactions predicted subsequent loss of the allergy [35].
●OFC was essential to determine the loss of allergy with certainty as some patients still reacted even when their SPTs and/or in vitro tests became completely negative. This may occur in as many as 10 percent of patients in such studies [97].
●Tolerance of peanut does not imply tolerance of tree nuts or seeds. In patients who outgrow peanut allergy, tree nut allergy or seed allergy can persist or subsequently develop for the first time [98]. Potential allergy to these foods must be independently evaluated.
Recurrence — Recurrences have been reported in patients thought to have outgrown peanut allergy, although this is unusual. Recurrence of tree nut allergy has not been studied. Infrequent ingestion of peanut may be a risk factor for recurrence/resensitization, but these data are derived from small numbers of cases.
In a follow-up of two studies, 62 of 64 patients who passed challenges subsequently ate peanut, but most did so infrequently (ie, once a month or less) [76,78]. There were two possible cases of recurrent reactions. In a third study, recurrent reactions were found in 3 of 36 patients (8 percent) with a clear history of peanut allergy who had previously passed a peanut OFC [99]. An example of a case was a six-year-old girl who had presented at age one year with generalized urticaria and facial angioedema within five minutes of eating a peanut butter cracker. Her PN-IgE level at diagnosis was 2.79 kUA/L, and she had no history of other food allergies. At age 4.5 years, her PN-IgE level was 1.1 kUA/L, and she passed peanut OFC. She subsequently ate only "may contain peanut" products until approximately 1.8 years after the initial OFC, when she had two bites of Butterfinger ice cream and within 15 minutes developed urticaria, coughing, difficulty breathing, throat tightness, abdominal pain, vomiting, and diarrhea. A repeat PN-IgE level was >100 kUA/L. An SPT was not performed, and a DBPCFC was deferred because of the severity of the reaction and the high PN-IgE level.
In this and several other small series of patients with resolved peanut allergy, it appears that recurrence may be more common among those who continue to avoid peanut or eat it infrequently [76,78,99,100]. In the study previously discussed, each of the three patients with recurrent allergy consumed concentrated peanut products less than once a month [99]. In contrast, none of a group of 23 patients who ate peanut more frequently had recurrent allergy.
Wheat allergy — Wheat allergy is a common childhood food allergy that is usually outgrown by adolescence [101-103]. Concomitant atopic disease and other food allergies are frequently seen [101]. The diagnosis and management of allergy to wheat and other grains are discussed in greater detail separately. (See "Grain allergy: Clinical features, diagnosis, and management".)
Wheat allergy related to occupational exposure in adults is also discussed separately, as is wheat allergy in association with exercise-induced anaphylaxis and celiac disease (gluten-sensitive enteropathy). (See "Respiratory manifestations of food allergy" and "Exercise-induced anaphylaxis: Clinical manifestations, epidemiology, pathogenesis, and diagnosis", section on 'Wheat-dependent EIA' and "Epidemiology, pathogenesis, and clinical manifestations of celiac disease in children" and "Management of celiac disease in children".)
Prevalence — IgE-mediated wheat allergy affects 0.1 to 1 percent of children in the United States and Europe, where wheat is a staple in the diet [3,11,25,104,105]. There are less data from Asia, where, in three surveys, the rate of wheat allergy ranged from 0.08 percent in Korea to 0.21 to 0.37 percent in Japan [106].
Resolution — Wheat allergy resolves by adolescence in most patients. Earlier resolution is seen in the general population followed by pediatricians compared with referred patient populations seen at tertiary-care centers. Peak wheat-specific IgE has some predictive value in determining the age at which tolerance develops, and higher levels may indicate risk of persistent allergy.
In studies of children with food allergy and atopic dermatitis, wheat allergy was outgrown in 25 and 33 percent of children over a one- and two-year follow-up, respectively [107,108]. In the general population, wheat allergy resolves in 80 percent of patients by five years of age [102]. However, tolerance appears to develop more slowly in a highly atopic population followed at a tertiary-care center, as is seen in similar populations with CMA and HEA [101].
A retrospective study examined the natural course of IgE-mediated wheat allergy in 103 children followed at a large referral center from 1993 to 2007 [101]. OFCs to wheat were performed in 61 percent during the study period. The median age at which tolerance was acquired was 6.6 years. However, the median age at resolution varied considerably depending upon peak wheat IgE (approximately 2, 4, and 10 years of age for children with peak wheat IgE levels <20, 20 to 50, and >50 kUA/L, respectively). Overall, tolerance was achieved by 29, 56, and 70 percent at 4, 8, and 14 years of age, respectively. In children aged two to eight years, the median wheat IgE levels associated with resolved allergy ranged from 21 to 25 kUA/L, whereas the median levels associated with persistent allergy ranged from 62 to 70 kUA/L. Patients with wheat sensitization (wheat IgE >20 kUA/L but no history of symptomatic exposure) passed OFCs at rates similar to the children discussed above who had a history of symptomatic wheat allergy.
Other foods — The natural history of other food allergies is less well studied.
Earlier studies suggested that soy allergy is typically outgrown in the preschool-age years [28,107-109]. However, a subsequent, larger, retrospective study performed at a tertiary-referral clinic found that only approximately 50 percent of children had outgrown soy allergy by seven years of age [110]. Soy allergy resolved in 25, 45, and 69 percent by age 4, 6, and 10 years, respectively.
The limited data available suggest that sesame allergy, similar to peanut and tree nut allergies, is more likely to persist [111-114]. The reported rate of resolution of sesame allergy ranges from 20 to 30 percent.
In one series of 30 children with lentil allergy, the median age of onset was 1.5 years, and the allergy had resolved in 50 percent by 3.5 years of age [115].
As mentioned previously, adverse reactions to fruits, vegetables, and other cereal grains are typically very short lived in children [64,109,116]. Many of these reactions may represent intolerances or irritant reactions rather than true allergy, and most children will lose their sensitivity to these foods within a period of 6 to 12 months. A minority of children have severe, IgE-mediated allergies to these foods that may persist over time, however. Children may also develop oral allergy syndrome (food-pollen allergy syndrome). (See 'Prevalence of childhood food allergy' above and "Clinical manifestations and diagnosis of oral allergy syndrome (pollen-food allergy syndrome)".)
There are few studies addressing the natural history of seafood (fish and shellfish) allergies. These can develop in childhood, although adult onset is believed to be more common. Seafood allergies are reviewed separately. (See "Seafood allergies: Fish and shellfish".)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Food allergy".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Beyond the Basics topic (see "Patient education: Food allergen avoidance (Beyond the Basics)")
SUMMARY AND RECOMMENDATIONS
●Prevalence and atopic march – The peak prevalence of food allergy is approximately 6 to 8 percent at one year of age and then falls progressively. By late childhood, the prevalence is 3 to 4 percent and remains stable thereafter. Children with food allergy are at high risk for developing later allergic rhinitis and asthma. (See 'Prevalence of childhood food allergy' above and 'Association with subsequent asthma and allergic rhinitis' above.)
●Natural history – Most childhood food allergies are lost during childhood or adolescence, although certain allergies tend to persist, such as those to fish/shellfish and peanut/tree nut. (See 'Overview of resolution' above.)
●General monitoring of the child with food allergy – Optimal monitoring of the child with food allergies requires the cooperative input of both the general pediatrician (to assess growth and development) and the allergy specialist (to address ongoing education, proper medication use, and reevaluate allergic status), as well as a dietitian in children with allergies to multiple foods that are staples in the diet. (See 'Monitoring the child with food allergy' above.)
●Serial testing – Most allergy experts use a combination of historical information from accidental exposures and periodic in vitro and/or skin testing. As an example, a challenge may be offered at a higher specific immunoglobulin E (IgE) level if there is a history of a recent accidental exposure without a reaction. Alternatively, a challenge will not be offered when the specific IgE is below the designated cutoff level but the patient has had a recent exposure that triggered a reaction. (See 'Serial testing' above.)
●Oral food challenge – An oral food challenge (OFC) medically supervised by an allergy specialist is recommended to confirm that a food allergy has resolved since in vitro and skin tests can remain positive in patients who achieve clinical tolerance and, conversely, tests can become negative in patients who still react upon ingestion, although the latter situation is uncommon. (See 'Determining if an allergy has resolved' above.)
●Cow’s milk allergy – Cow's milk allergy (CMA; all types) affects approximately 2.5 percent of children under two years of age. The most common forms of non-IgE-mediated CMA are transient childhood conditions that are almost always outgrown, with the exception of eosinophilic esophagitis. IgE-mediated CMA may persist into adolescence, although it is usually outgrown by adulthood. (See 'Cow's milk' above.)
●Hen's egg allergy – Hen's egg allergy (HEA) affects 1 to 9 percent of children. The majority of cases resolve by adulthood. (See 'Hen's egg' above.)
●Peanut and tree nut allergies – Peanut and tree nut allergies affect approximately 0.5 to 3 percent of children and may be increasing over time. It is likely to be a lifelong disorder for most patients, although 20 to 25 percent outgrow peanut and at least 9 percent outgrow tree nut allergies. Recurrence is rare, although a few cases have been documented. (See 'Peanut and tree nuts' above.)
●Wheat allergy – Wheat allergy is a common childhood food allergy that is usually outgrown by adolescence. Concomitant atopic disease and other food allergies are frequently seen. (See 'Wheat allergy' above.)
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